This R21 application is in response to the program announcement PA-04-119. Influenza is a category C (emerging infectious disease) pathogen on the NIH bioterror pathogen list. Every year, naturally occurring influenza causes approximately 36,000 deaths in the United States alone. Over 90% of these deaths occur in the elderly population. The consequences of a pandemic or an engineered influenza attack would be devastating to this age group. This greatly disproportionate death rate is largely due to the normal, age- related decrease in immune vigor. Vaccine production against new flu strains takes a minimum of six months, and the current influenza vaccine is only of limited efficacy in people who are 65 years or older. Any improvement in influenza vaccine strategies would be of particular benefit to the elderly. By employing a novel antigen-targeting system that functions at the crossroads between adaptive and acquired immunity, we hope to stimulate protective heterosubtypic influenza immunity in the aged. This adjuvant is a response- selective agonist of the C5a receptor. Antigen coupled to this C5a agonist can induce innate, humoral and cellular immune response. Using a well-established mouse model, the first specific aim will examine the immune responses generated by young and aged animals following vaccination with the C5a agonist coupled directly to the influenza virus. We will examine the CD4, CDS, B cell, and natural killer cell responses in detail, comparing the aged immune response against that achieved in the young. In the second aim, the knowledge gained from the first aim will be used to examine protection against influenza challenge in the aged, as compared to protection mediated through the conventional vaccine. [unreadable] [unreadable] [unreadable]